Anti-inflammatory,antalgic and antipyretic medicament,on a pyridoxine flufeenamate basis

ABSTRACT

An anti-inflammatory, antalgic and anti-pyretic medicament contains pyridoxine flufenamte and an excipient to which may be added several compatible constituents such as vitamin B1.

United States Patent Sarbach et al.

ANTl-INFLAMMATORY, ANTALGIC AND ANTI-PYRETIC MEDICAMENT, ON A PYRIDOXINE FLUFENAMATE BASIS Inventors:

Assignee:

Filed:

AppL. N0.:

Institut De Recherche Scientifigue (I.R.S.), Chatillon-sur-Chalorrone, France Dec. 7, 1971 7 Related U.S. Application Data Continuation of Ser. No. 58,147, July 24, 1970, Pat. No. 3,627,774.

I Foreign Application Priority Data July 24, 1969 France .f. ..6925 288 51 Feb. 13,1973

[52] U.S. Cl ..424/263 [51] Int. Cl. ..A61u 27/00 [58] Field of Search ..424/263 [56] References Cited UNITED STATES PATENTS 3,206,463 9/1965 Baetz ..260/295 VB 3,418,416 12/1968 Fourneaum ..260/295 VB Primary Examiner-Stanley J. Friedman Att0rney--Alvin Browdy et al.

[57] ABSTRACT An anti-inflammatory, antalgic and anti-pyretic medicament contains pyridoxine flufenamte and an excipient to which may be added several compatible constituents such as vitamin B 9 Claims, No Drawings ANTI-INFLAMMATORY, ANTALGIC AND ANTI- PYRETIC MEDICAMENT, ON A PYRIDOXINE FLUFENAMATE BASIS This application is a'continuation of parent application Ser. No. 58,147 filed July 24, 1970, now US. Pat. 5 No. 3,627,774. 1

The object of this invention is the introducing of pyridoxine flufenamate in human and veterinary' therapy, said new body being endowed with anti-inflammatory, antalgic and anti-pyretic properties. Pyridoxine flufenamate has also some of the biologic and pharmacodynamic properties of vitamin B Pyridoxine flufenamate is basically dealt with hereinafter, however said body may be replaced by similar by-products from other B vitaminic factors, such as: pyridoxamine, pyridoxal, it being understood that said bodies have the same therapeutic properties l OHNa NH@ HaC HHmFzNO: 281.3

as those indicated above.

Pyridoxine flufenamate is prepared according to standard medicinal weight and is presented, neat or in compatible mixture, under an approved pharmaceutical form, for instance in the form of tablets or capsules, or also in the form of suspension, suppositories, pomade, etc.

The formula of said body is indicated hereunder:

i.e.: C H F N 0 Molecular weight: 450.41

Base pyridoxine: 37.56 percent Flufenamic acid: 62.44 percent The formulas of the corresponding salts of pyridoxamine or of pyridoxal are obtained by replacing in the above formula:

2 1- PiiEPARATloN PROCESS First preparation process.

In a 250 ml. stoppered erlenmeyer, is poured 7.025 g. (0.025 mole) of flufenamic acid with 50 ml. of methanol. Then base pyridoxine is added (4.229 g. 0.025 mole). The mixture is stirred mechanically for 5 minutes. The methanol is evaporated by means ofa vacuum revolving evaporator and of a water-bath at 40 C.

As soon as a white cream foam is formed, the vacuum is cut off.

The mixture is then vacuum dried for 2 hours at 30- 35 C.

The product is crushed and vacuum dried again for 1 night without heating and secured from moisture.

Second preparation process.

The reaction is indicated hereunder:

OHzOH OF; HO

CH OH l CIH 40 CxHnNOa-CIH 205.64

(11112011 nofiornou @'-ooorr or. H3O NH Preparation process: I I Q I H A warm solution containing 2.81 g (0.01 mole) of flufenamic acid is added while being stirred in 20 ml. of water containing 0.40 g. (0.01 mole) of soda to a solution containing 2.06 g. (0.01 mole) of pyridoxine hydrochlorate in 15 ml. of water. The product crystallizes immediately and is placed into a refrigerator during 1 hour or 2. The product is then dried, washed with water and vacuum dried.

Thereby, 3.42 g. of pale greenish yellow crystals is obtained (yield: 76 percent); upon the recrystallization in ethanol at percent and in water in presence of carbon, crystals remain colored.

Il PROPERTIES III' TOXICOLOGIC AND PHARMACOLOGICAL SURVEY This survey includes:

1 Determination of toxicity 2 Determination of anti-inflammatory power 3 Determination of antalgic power 4 Determination of antipyretic power A. TOXICITY This survey is conducted with 40 male Charles River miceweighing between 19 and 21 g., and shared out into four batches of 10 mice.

Each batch is given orally, and with volume of 0.5 ml./20 g. one of the following doses of pyridoxine flufenamate 800, 1,200, 1,800, 2,700 mg/kg in suspension into carboxymethyl cellulose at 0.5 percent.

' Mice are kept under watch during 5 days after which toxicity is noted.

Results are indicated hereunder:

Pyridoxine flufenamate 800 mg/kg I200 1800 2700 sl s s i; s s

Death rate l0% 40% 70% 80% A DL 50 equal to 1,500 mg/kg appear from these results.

B. ANTI-INFLAMMATORY POWER Anti-inflammatory research is conducted on a rat leg oedema caused by intraplantar injection containing 0.50 ml. of carragenin solution at 1 percent.

Forty l 125 g male Charles River rats are thus divided into one test batch of 10 animals and three processed batches of 10 animals each. The treatment is given orally by means of a suspension 1 hour before the carragenin injection.

Pyridoxine flufenamate doses used are as-follows:

4.8, 14.4 and 43.2 mg/k'g.

Under these conditions, the DE rate is 45 mg/kg.

c. ANTALGIC POWER 0N MlCE The test used is that of SlEGMUND. 7

An intraperitoneum injection of phenylbenzoquinone made on a mouse causes a painful syndrome which materializes by abdomen contortions.

Twelve male 19 21 g. Charles River mice are used Under these conditions, the DE 50 rate is 300 rug/kg.

D. ANTIPYRETIC POWER Over-temperature is caused to rats by subcutaneous injection of l0 ml/kg of harm in suspension at percent.

Three batches of IO male 180 200 g. Charles River rats are made. v

Batch 1 Test batch Batch 2 Pyridoxineflufenamate at 80 mg/kg Batch 3 Pyridoxine flufenamate at 320 mg/kg The treatment is carried out 4 hours after the injection of barm. Temperatures are read just before the beginning of the treatment and then every hour during 4 hours.

Results Average temperature variations as from the beginning of the treatment Number of hours Tests Pyridoxine after treatment flufenamate Pyridoxine mg/kg flut'enamate I60 rnglkg l 07C 0 0 2 08C 0lC -02C 3 llC 0 03C 4 12C 0 -0lC Accrued variations 38C 0lC 06C immediately after the 80 mg/kg dose, the pyridoxine flufenamate hinders the progress of over-temperature resulting from the injection of barm. Findings Pyridoxine flufenamate has outstanding anti-inflammatory anti-pyretic' and antalgic properties.

its therapeutic index DL SOIDE S0 is high, particularly as concerns anti-inflammatory power and also antipyretic power.

IV HUMAN AND ANIMAL THERAPEUTIC USE EXAMPLE On the basis of the pharmacodynamic and toxicologic collected and set forth hereinabove, pyridoxine flufenamate possesses definite anti-inflammatory, antalgic and antipyretic properties.

Rheumatology is an excellent field for the use of the medicament.

Pyridoxine flufenamate is also especially recommended for treatment of neuritis, polyneuritis, cholecystis, etc., cases to which the various above mentioned properties as well as specific properties of B vitamin are applicable all together.

In the case of neuritic diseases with an adult, 1.50 to 2 g. of pyridoxine flufenamate may be given at the rate of three or four doses per day at regular intervals dur ing the nycthemer.

The active constituent for these uses can appear under various pharmaceutical forms: tablets, capsules, suppositories titrated at 250, 375, 500 mg.

Pyridoxine flufenamate may be given to children. In the case of rheumatic algy, for instance, l0 mg. per kilo of weight and per day will be prescribed, preferably under the form of syrup, of powder or granules titrated at 1 or 2 percent of active constiment.

According to specific directions, pyricloxine flufenamate may be associated with one or several other compatible active constituents, such as B, vitamin, for instance.

The medicament may also be used for anti-inflammatory, antalgic and anti-pyretic treatments with animals, particularly dogs, cats, horses, cattle and sheep.

Medicaments according to the invention include the following:

Tablets Pyridoxine flut'enamate 375 mg.

Excipient: q.s.p. one tablet Capsules Pyridoxine flufenamate 250 mg.

Excipient: q.s.p. one capsule Syrups Pyridoxine flufenamate l g.

Excipient: q.s.p. 100 g. of syrup Granules Pyridoxine flufenamate 2 g.

Excipient: q.s.p. 100 g. of granules Suppositories Pyridoxine flufenamate: 500 mg.

Excipient: q.s.p. one suppository Coated tablet Pyridoxine flufenamate 0.160 g.

Excipient: q.s.p. a tablet Excipients which may be used include sugar, corn starch, PVP, magnesium stearate, gum lac, alcohol 95, ventilated talc, gum arabic, titanium dioxide, sunyellow coloring and tartrazine.

Following are some specific examples of the inven- TABLETS Pyridoxine flufenamate 0.160 g. Sugar 0.125 g. Corn starch 0.050 g. Polyvinylpyrrolidone 0.005 g. Modified starch 0.050 g. Magnesium stearate 0.010 g. (for a tablet of about 0.400 g.)

C APSULES Pyridoxine flufenamate 0.160 g. Icing sugar 0.150 g. Modified starch 0.050 g. Magnesium stearate 0.002 g. Silicone talc at 0.5% 0.002 g. (for a gelule No. 0)

SYRUP Pyridoxine flufenamate l g. Lump sugar 30 g. P-carraghenate 0.9 g. Soda nipagine 0.150 g. Soda nipasol 0.020 g. Pure quince fruit flavor 4 g. Scarlet coloring 0.012 g. Pennuted water q.s.p. 100 ml.

GRA NULES Pyridoxine flufenamate 2 g. Icing sugar 66 g. Com starch 30 g Polyvinylpyrrolidone 2 g. q.s.p. 100 g of granules SUPPOSITORIES Pyridoxine flufenamate 0.500 g. Semi-synthetic glycerides 2.500 g. (for a suppository of about 3 g.)

COATED TABLETS Pyridoxine flufenamate 0.160 g.

ugar 0.125 g. Corn starch 0.050 g. Polyvinylpyrrolidone 0.005 g. Ma nesium stearate 0.010 2g She lac 0.007 g Ethyl-alcohol at 95 0.0164 g Gum-arable 0.0014 g Titanium oxyde 0.0024 g. Sun yellow coloring 0.00012 g. Tartrazine 0.00006 g. Modified starch 0.050 g. Sugar q.s.p. a coated tablet of 0.550 g.

A specific example of a composition with vitamin B1 added is as follows:

(for a tablet of about 0.450 g.)

Thirty patients having acute or chronic rheumatisms have been treated with four to six tablets a day, the treatment duration varied from 8 days to 3 months.

The analysis of the so treated cases have shown a beneficial action extending from the total vanishing of the clinical manifestations up to the diminishing of the dolorous, stiffening or lameness phenomena.

This action was revealed in cases of:

inflammatory rheumatisms (anchylosing spondylarthritis, rheumatoid polyarthritis, psoriasic rheumatism).

arthrosis (gonarthrosis, 'Bouchard dosarthrosis) radiculalgies (sciatic, arvicobrachial) humeral scapulo periarthritis lombalgies A particularly good tolerance of this medicament was found in percent of the cases.

rheumatism Examples of Clinical Cases Case No. 1:

Name: PEN Jean Republican guard 37 years Admitted to an hospital for left sciatic radiculalgy. Four tablets a dayfor 25 days. Excellent results. Treatment stopped after recovery. Excellent clinical and biological tolerance. Case No. 2:

Name: PRE Sabin Office Clerk 47 years Admitted to an hospital for dolorous outbreak o dorsal arthrosis Four tablets a day for 20 days. Excellent results. Full vanishing of the pains. Good tolerance. Case No. 3:

Name: POI Pierre Colonel 56% years Admitted to an hospital for psoriasic rheumatism. Six tablets a day for 25 days. Excellent results, vanishing of the pains. Excellent tolerance.

Case No. 4

Name: GUI Henri Student 22 years Admitted to an hospital for anchylosing spondilarthritis Six tablets a day for 13 days Good results Vanishing of the nocturnal lumbar spondaneous pains and of the two wrist pains.

What is claimed is:

1. A medicament comprising as active ingredient a compound of the formula wherein X represents a member selected from the group consisting of CH,OH, CH,,--Nl-l and CH=O, and an excipient said active ingredient being present in an effective amount to provide anti-inflammatory, antalgic or anti-pyretic action.

2. A medicament in accordance with claim 1 wherein said medicament is in the form of a tablet.

3. A medicament in accordance with claim 1 wherein said active ingredient is present in an amount of about 0.160 0.375 g.

4. A medicament in accordance with claim 1 wherein said medicament is in the form of a capsule.

5. A medicament in accordance with claim 1 wherein said medicament-is in the form ot'. a syrup. 4

6. A medicament in accordance with claim 1 wherein said medicament is in-the form of granules.

7. A medicament in accordance with claim 1 wherein said medicament is in the form of a suppository.

8. A medicament in accordance with claim 1 further including vitamin B 1.

9. A medicament in accordance with claim 8 which contains 0.160 g; of said active ingredient and 0.050 g. of vitamin B 

1. A medicament comprising as active ingredient a compound of the formula
 2. A medicament in accordance with claim 1 wherein said medicament is in the form of a tablet.
 3. A medicament in accordance with claim 1 wherein said active ingredient is present in an amount of about 0.160 - 0.375 g.
 4. A medicament in accordance with claim 1 wherein said medicament is in the form of a capsule.
 5. A medicament in accordance with claim 1 wherein said medicament is in the form of a syrup.
 6. A medicament in accordance with claim 1 wherein said medicament is in the form of granules.
 7. A medicament in accordance with claim 1 wherein said medicament is in the form of a suppository.
 8. A medicament in accordance with claim 1 further including vitamin B1. 